Feature Articles

Single-Use Systems Become the Norm

Awareness of Economic Benefits Has Propelled This Trend

Over the last few years, disposable biomanufacturing has shed its reputation for isolated, low-tech storage and hold applications to an over-arching strategy appropriate for every stage in a product’s manufacturing life cycle. Aiding this trend have been awareness of the economic benefits of disposable equipment, the remarkable rise in titers from cell culture processes, and—to a lesser degree—a focus away from blockbusters and toward personalized medicine and orphan drugs.

Spencer Parkinson, senior product manager for single-use systems at Thermo Fisher Scientific, was not surprised to see that virtually every session at “BioProcess International” included presentations on disposables. “Just a few years ago we had to convince people of the compelling economic argument for disposables,” he said, “but now it’s becoming the norm, the predominant way of thinking of bioprocessing.”

Companies with large investments in stainless steel equipment may still hold back depending on the size of their investment, and globally, Asia appears to lag behind the U.S. and Europe in its adoption of disposables since “economics vary in different regions.” But the cost and flexibility arguments are compelling for new projects and facility expansions.

The trend toward ever larger single-use equipment notwithstanding, Parkinson does not believe there will be great demand for bioreactors larger than 2,000 liters. High titers and smaller batches are already eroding the need for mega-bioreactors, he says. “There are, of course, occasions where larger cell cultures are required, and that will continue, but there’s already enough capacity out there in stainless steel to handle that.”

Separations

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ESEM image of Natrix Separations’ Weak C Media: ESEM images are taken under a controlled atmospheric pressure (of moisture in this case). Standard high vacuum SEM images of the firm’s media result in a collapsed hydrogel structure, which are only of limited use for structural interpretation.

Bernd H. A. Rehm, Ph.D., chief scientific officer at PolyBatics, addressed the need for lower-cost affinity media. PolyBatics, which specializes in customizable and/or biodegradable polymer beads for antigen delivery, biocatalysis, and medical diagnostics, recently developed beads that express the IgG binding domain of protein A at high density. Part of a fusion protein, the “ZZ” domain is crosslinked to the core of the polyester beads. “The binding capacity is approximately double that of commercially available protein A resins,” Dr. Rehm said.

PolyBatics employs engineered microorganisms to produce highly functional beads with superior binding capacities and affinities cost-effectively, according to Dr. Rehm. In addition to bioseparations, beads can be constructed for other useful protein-mimicking functions, for example enzymatic catalysis or antigenicity (as in vaccines).

What about cost? “That’s confidential,” he said, “but the current low production costs suggest a use as single-use resins.” If PolyBatics can demonstrate clear-cut economic advantages, new processes will have the benefit of fully disposable chromatography as well as single-use upstream equipment during development and beyond.

Membrane chromatography is a single-use technology traditionally used to remove trace impurities, as in polishing. But C. Howie Honeyman, Ph.D., vp of R&D at Natrix Separations, showed how membranes can compete with traditional chromatography resins. He described novel membranes with high binding capacity and throughput, suitable for bind-and-elute processing.

The Natrix membranes consist of a polymeric hydrogel formed within a flexible porous support matrix. The matrix provides mechanical strength, while the hydrogel dictates the product’s separation chemistry. The gel provides high binding-site density, high surface-binding area, and high mass transfer. The two components can be optimized independently, yielding a low-cost, high-performance membrane product, Dr. Honeyman said.

So far Natrix offers the membranes in cation- and anion-exchange formats that exceed those of membrane capacities by up to a factor of eight and often, on a by-weight basis, resin capacities as well. A test case presented at the conference showed a conventional resin binding approximately 20 mg/mL of an IgG at 10% breakthrough, while the Natrix C material bound 100 mg under the same conditions.

“The membranes are a perfect combination of high surface area, convective flow channels, and high functional group density,” said Dr. Honeyman. “Convective flow gives high throughput, while high surface area and high functional group density provides high binding capacity.” Natrix is looking into a carboxylic acid-based resin and affinity materials as well. “We’re particularly interested in developing a protein A and IMAC nickel chemistry.”

For large-scale, high-titer processes, four membranes, employed with the right fluid handling and recycling, could process products from a 20,000 liter bioreactor, according to Dr. Honeyman. Or, he said, each membrane may be “campaigned” by processing 400 liters at a time through five bind/elute cycles.

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